The focus of the current proposal is the mammalian Na+/dicarboxylate co-transporter, NaDC-1, which is expressed on the apical membranes of the epithelial cells of the small intestine and kidney proximal tubule. NaDC-1 transports the metabolic intermediates of the Krebs cycle, including citrate and succinate. This transporter is the mammalian homolog of the Drosophila Indy gene product that has been implicated in determining lifespan. Mutations that lead to a partial inactivation of Indy produce an increase in lifespan, similar to the effects of caloric restriction in mammals. The results suggest that a reduction in the activity of NaDC-1 by inactivation or by reducing its substrates may produce the metabolic changes that lead to increased longevity. The long-term objective of this research is to determine the feasibility of using NaDC-1 as a target protein to mimic the effects of caloric restriction. Our group has a longstanding interest in the transporters related to NaDC-1 and we have cloned the NaDC-1 orthologs form human, rabbit and mouse. The studies in this proposal will use the cDNAs coding for the mouse and human NaDC-1 to produce preliminary data in two areas: first, relating the activity of NaDC-1 in aging and caloric restriction, and second, identifying factors that regulate the activity of NaDC-1.